The Duke-UNC-Stanford Center for Mouse Models of Diabetic Complications consists of a multi-disciplinary group of investigators with substantial experience in genetic engineering, in molecular and physiological phenotyping in mice, and in the study of rodent models of diabetes. Based on our cumulative expertise, we propose to study two diabetic complications: nephropathy and vascular disease. We recognize the deficiencies of current mouse models of diabetic complications including relatively mild severity that does not progress to recapitulate the pathology seen in the later stages of human diabetes. We hypothesize that this lack of congruity with human disease is not due to a fundamental difference in biology, but instead is due to the presence or absence of genetic factors that modulate susceptibility to end-organ injury. Therefore, in our proposals for model development, we will introduce genetic alterations into diabetic mice with the aim of exaggerating the severity of kidney and vascular disease. These proposed alterations fall into two categories. First are genetic changes that cause hypertension. Hypertension is a common accompaniment of diabetes and control of blood pressure can ameliorate the development of diabetic complications in humans. Our genetic hypertension models differ in the level of involvement of the renin-angiotensin system so that the actions of elevated blood pressure can be separated from those of angiotensin II. Secondly, we will generate diabetic mice with genetic alterations that enhance formation or actions of reactive oxygen species, another pathway that has been suggested to promote human diabetic complications. To achieve our aims of developing and characterizing mouse models of diabetic complications, we also propose three technical innovations: (1) To generate embryonic stem cell lines from diabetic mouse strains to facilitate genetic manipulation. (2) To produce mice with "humanized" susceptibility loci for diabetic complications as they are identified in human genetic studies. (3) To develop molecular phenotyping for sensitive detection of changes in gene expression associated with diabetic end-organ damage. We plan to share these technologies fully with other investigators to help accomplish the overall goals of the Mouse Models of Diabetic Complications Consortium.